Renin angiotensin system (RAS) is well established as having a crucial role in cardiovascular and renal diseases. Most persuasive are the accumulating data in animal models as well as in clinical trials affirming the renoprotective effects of antagonizing angiotensin II (Ang II) generation or actions. Interestingly, RAS activity can be modulated by genetic variations of RAS components. In particular, an insertion/deletion polymorphism (I/D) in the human angiotensin I converting enzyme (ACE) gene affects the level of circulating ACE; moreover, homozygous deletion (DD) predicts several cardiovascular disease and progressive deterioration in some glomerular disease, including IgA and diabetic nephropathies. Our projects will test the hypothesis that genetic variations in RAS, particularly the ACE I/D variant, predicts progressive renal damage in a non-glomerular injury, namely congenital uropathies, where RAS has a crucial role. This entity is an important cause of renal damage in children. We further plan to define pathways by which the genetic variant influences downstream events pivotal in progressive renal damage. In view of the apparant heterogeneity in the impact of ACe I/D on ACE activity among organs, we hypothesize that there is a tighter association between ACE polymorphism and renal (vs systemic) ACE activity. Moreover, the purpose that ACE I/D drives other Ang-mediated factors important in tissue damage such as proteinases, e.g., plasminogen activator inhibitor (PAI) and tissue inhibitor of metalloproteinase (TIMP), The hypothesis that local renal ACE (and downstream modulators PAI/TIMP) is pivotal in the renal response to injury will be directly studies in a genetically engineered mouse characterized by regional difference in levels of ACE activity. Finally, mutagenesis studies in human cell lines will define the functional consequence of a putative regulatory element in the ACE I/D locus.